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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Gen+Physiol
2014 ; 144
(4
): 337-48
Nephropedia Template TP
J Gen Physiol
2014[Oct]; 144
(4
): 337-48
PMID25225551
show ga
The epithelial Na(+) channel (ENaC) functions as a pathway for Na(+) absorption
in the kidney and lung, where it is crucial for Na(+) homeostasis and blood
pressure regulation. However, the basic mechanisms that control ENaC gating are
poorly understood. Here we define a role in gating for residues forming
interfaces between the extracellular domains of the three ENaC subunits. Using
cysteine substitution combined with chemical cross-linking, we determined that
residues located at equivalent positions in the three subunits (?K477, ?E446, and
?E455) form interfaces with residues in adjacent subunits (?V85, ?V87, and ?L120,
respectively). Cross-linking of these residues altered ENaC activity in a
length-dependent manner; long cross-linkers increased ENaC current by increasing
its open probability, whereas short cross-linkers reduced ENaC open probability.
Cross-linking also disrupted ENaC gating responses to extracellular pH and Na(+),
signals which modulate ENaC activity during shifts in volume status. Introduction
of charged side chains at the interfacing residues altered ENaC activity in a
charge-dependent manner. Current increased when like charges were present at both
interfacing residues, whereas opposing charges reduced current. Together, these
data indicate that conformational changes at intersubunit interfaces participate
in ENaC transitions between the open and closed states; movements that increase
intersubunit distance favor the open state, whereas the closed state is favored
when the distance is reduced. This provides a mechanism to modulate ENaC gating
in response to changing extracellular conditions that threaten Na(+) homeostasis.
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